Emergent data from public health and clinical epidemiological studies have provided convincing evidence for a new risk factor in obesity and type 2 diabetes mellitus: introduction of extended periods of wakefulness in the workplace and at home giving rise to temporal disruption between the external environment and internal integrative physiological systems coordinating feeding, nutrient storage and energy expenditure. In very recent large-scale association studies, polymorphisms in key genes involved in circadian processes have been implicated in glucose homeostasis at the genetic level in humans. Against this backdrop, a long-line of clinical and pre-clinical research into ingestive behavior and glucose metabolism has also shown that perturbations in the rhythmic control of both feeding and glucose turnover are hallmarks of dysmetabolic states; however the mechanistic links between circadian disruption, energetics and metabolism have remained obscure. A major breakthrough in our understanding of the impact of circadian disruption on integrative physiology originated in discoveries over the past 5 years that have uncovered a central role for the biological clock in the control of both body weight and metabolism. While the central tenet of circadian research prior to the 1990s held that the brain master pacemaker was the unitary center for mammalian timekeeping, a remarkable development has been the finding that core clock genes comprise a transcription-translation feedback loop oscillating every ~24 hrs in nearly all tissues in addition to the SCN. In 2005, we reported that ENU-derived Clock 19 mutant mice exhibit susceptibility to diet-induced obesity, altered day-night feeding patterns, hyperglycemia and, surprisingly, hypoinsulinemia; however, to date, our understanding of the tissue-specific roles of clock genes in feeding behavior and integrative physiology remains incomplete. In efforts to refine our knowledge of the local function of clock genes within both brain pacemaker neurons and in extra-SCN and peripheral locations, we have assembled a unique interdisciplinary team, and now propose to combine conditional tissue-specific gene targeting with an extensive platform for behavioral, physiological and molecular analyses. Based upon our exciting preliminary results which demonstrate feasibility of conditional knockout of clock function within either brain or pancreas, the forward-reaching goal of this proposal will be to determine the relative contribution of clock disruption within brain (Aim 1) or within endocrine pancreas (Aim 2) to the obesity and hyperglycemia observed in multi-tissue circadian mutants. Results from the proposed research will advance knowledge at the intersection of genes and behavior and provide new therapeutic targets and strategies to intervene in both obesity and diabetes mellitus. PUBLIC HEALTH RELEVANCE: Obesity and type 2 diabetes mellitus represent escalating public health challenges that threaten to erode advances in delivery and availability of healthcare throughout the US and the developing world. Our research proposal focuses on an exciting new discovery that disruption in the internal biological circadian timing system represents a major yet poorly understood risk factor in both obesity and diabetes-to this end, we propose a series of experimental studies using state-of-the-art technologies in order to unravel the brain and body functions of the endogenous clock system in both long-term weight control and glucose tolerance. Ultimately, our studies will lead to new therapeutic strategies and, at the public health level, insight gained from our work will enable behavioral modifications to improve metabolic health.